C10 heterosubstituted acetate taxane compositions

ABSTRACT

Compositions comprising a taxane having a heterosubstituted acetate substituent at C(10), a hydroxy substituent at C(7), and a range of C(2), C(9), C(14), and side chain substituents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 10/609,301 filed Jun. 27, 2003 now U.S. Pat. No. 6,872,837, which is a continuation of application Ser. No. 09/775,912 filed Feb. 2, 2001 now U.S. Pat. No. 6,664,275, which claimed priority from U.S. provisional application Ser. No. 60/179,669, filed on Feb. 2, 2000.

BACKGROUND OF THE INVENTION

The present invention is directed to novel taxanes which have exceptional utility as antitumor agents. The taxane family of terpenes, of which baccatin III and taxol are members, has been the subject of considerable interest in both the biological and chemical arts. Taxol itself is employed as a cancer chemotherapeutic agent and possesses a broad range of tumor-inhibiting activity. Taxol has a 2′R, 3′S configuration and the following structural formula:

wherein Ac is acetyl.

Colin et al. reported in U.S. Pat. No. 4,814,470 that certain taxol analogs have an activity significantly greater than that of taxol. One of these analogs, commonly referred to as docetaxel, has the following structural formula:

Although taxol and docetaxel are useful chemotherapeutic agents, there are limitations on their effectiveness, including limited efficacy against certain types of cancers and toxicity to subjects when administered at various doses. Accordingly, a need remains for additional chemotherapeutic agents with improved efficacy and less toxicity.

SUMMARY OF THE INVENTION

Among the objects of the present invention, therefore, is the provision of taxanes which compare favorably to taxol and docetaxel with respect to efficacy as anti-tumor agents and with respect to toxicity. In general, these taxanes possess a heterosubstituted acetate substituent at C-10, a hydroxy substituent at C-7 and a range of C-3′ substituents.

Briefly, therefore, the present invention is directed to the taxane composition, per se, to pharmaceutical compositions comprising the taxane and a pharmaceutically acceptable carrier, and to methods of administration.

Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In one embodiment of the present invention, the taxanes of the present invention correspond to structure (1):

wherein

R₂ is acyloxy;

R₇ is hydroxy;

R₉ is keto, hydroxy, or acyloxy;

R₁₀ is heterosubstituted acetate;

R₁₄ is hydrido or hydroxy;

X₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo;

X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀;

X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo;

Ac is acetyl; and

R₇, R₉, and R₁₀ independently have the alpha or beta stereochemical configuration.

In one embodiment, R₂ is an ester (R_(2a)C(O)O—), a carbamate (R_(2a)R_(2b)NC(O)O—), a carbonate (R_(2a)OC(O)O—), or a thiocarbonate (R_(2a)SC(O)O—) wherein R_(2a) and R_(2b) are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. In a preferred embodiment, R₂ is an ester (R_(2a)C(O)O—), wherein R_(2a) is aryl or heteroaromatic. In another preferred embodiment, R₂ is an ester (R_(2a)C(O)O—), wherein R_(2a) is substituted or unsubstituted phenyl, furyl, thienyl, or pyridyl. In one particularly preferred embodiment, R₂ is benzoyloxy.

While R₉ is keto in one embodiment of the present invention, in other embodiments R₉ may have the alpha or beta stereochemical configuration, preferably the beta stereochemical configuration, and may be, for example, α- or β-hydroxy or β-acyloxy. For example, when R₉ is acyloxy, it may be an ester (R_(9a)C(O)O—), a carbamate (R_(9a)R_(9b)NC(O)O—), a carbonate (R_(9a)OC(O))-), thiocarbonate (R_(9a)SC(O)O—) wherein R_(9a) and R_(9b) are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. If R₉ is an ester (R_(9a)C(O)O—), R_(9a) is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, subsituted or unsubstituted aryl or substituted or unsubstituted heteroaromatic. Still more preferably, R₉ is an ester (R_(9a)C(O)O—), wherein R_(9a) is substituted or unsubstituted phenyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, or subsituted or unsubstituted pyridyl. In one embodiment R₉ is (R_(9a)C(O)O—) wherein R_(9a) is methyl, ethyl, propyl (straight, branched or cyclic), butyl (straight, branched or cyclic), pentyl, (straight, branched or cyclic), or hexyl (straight, branched or cyclic). In another embodiment R₉ is (R_(9a)C(O)O—) wherein R_(9a) is substituted methyl, substituted ethyl, substituted propyl (straight, branched or cyclic), substituted butyl (straight, branched or cyclic), substituted pentyl, (straight, branched or cyclic), or substituted hexyl (straight, branched or cyclic) wherein the substituent(s) is/are selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.

In one embodiment, R₁₀ is R_(10a)C(O)O— wherein R_(10a) is heterosubstituted methyl, said heterosubstituted methyl moiety lacking a carbon atom which is in the beta position relative to the carbon atom of which R_(10a) is a substituent. The heterosubstituted methyl is covalently bonded to at least one heteroatom and optionally with hydrogen, the heteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatom may, in turn, be substituted with other atoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety. Exemplary R₁₀ substituents include R_(10a)COO— wherein R_(10a) is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, acetoxymethyl, acyloxymethyl, or methylthiomethyl.

Exemplary X₃ substituents include substituted or unsubstituted C₂ to C₈ alkyl, substituted or unsubstituted C₂ to C₈ alkenyl, substituted or unsubstituted C₂ to C₈ alkynyl, substituted or unsubstituted heteroaromatics containing 5 or 6 ring atoms, and substituted or unsubstituted phenyl. Exemplary preferred X₃ substituents include substituted or unsubstituted ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl, and pyridyl.

Exemplary X₅ substituents include —COX₁₀, —COOX₁₀ or —CONHX₁₀ wherein X₁₀ is substituted or unsubstituted alkyl, alkenyl, phenyl or heteroaromatic. Exemplary preferred X₅ substituents include —COX₁₀, —COOX₁₀ or —CONHX₁₀ wherein X₁₀ is (i) substituted or unsubstituted C₂ to C₈ alkyl such as substituted or unsubstituted methyl, ethyl, propyl (straight, branched or cyclic), butyl (straight, branched or cyclic), pentyl (straight, branched or cyclic), or hexyl (straight, branched or cyclic); (ii) substituted or unsubstituted C₂ to C₈ alkenyl such as substituted or unsubstituted ethenyl, propenyl (straight, branched or cyclic), butenyl (straight, branched or cyclic), pentenyl (straight, branched or cyclic) or hexenyl (straight, branched or cyclic); (iii) substituted or unsubstituted C₂ to C₈ alkynyl such as substituted or unsubstituted ethynyl, propynyl (straight or branched), butynyl (straight or branched), pentynyl (straight or branched), or hexynyl (straight or branched); (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl, wherein the substituent(s) is/are selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.

In one embodiment of the present invention, the taxane corresponds to structure 1, X₅ is —COX₁₀ wherein X₁₀ is phenyl or —COOX₁₀ wherein X₁₀ is t-butoxycarbonyl, and R₁₀ is R_(10a)C(O)O— wherein R_(10a) is alkoxymethyl, preferably methoxymethyl or ethoxymethyl. In another embodiment of the present invention the taxane corresponds to structure 1, X₅ is —COX₁₀ wherein X₁₀ is phenyl or —COOX₁₀ wherein X₁₀ is t-butoxycarbonyl, and R₁₀ is R_(10a)C(O)O— wherein R_(10a) is acyloxymethyl, preferably acetoxymethyl.

In another embodiment of the present invention, the taxane corresponds to structure 1, X₅ is —COX₁₀ wherein X₁₀ is phenyl or —COOX₁₀ wherein X₁₀ is t-butoxycarbonyl, R₁₀ is R_(10a)C(O)O— wherein R_(10a) is alkoxymethyl such as methoxymethyl or ethoxymethyl, or aryloxymethyl such as phenoxymethyl, and X₃ is heterocyclo. In another embodiment of the present invention the taxane corresponds to structure 1, X₅ is —COX₁₀ wherein X₁₀ is phenyl or —COOX₁₀ wherein X₁₀ is t-butoxycarbonyl, and R₁₀ is R_(10a)C(O)O— wherein R_(10a) is acyloxymethyl, preferably acetoxymethyl, and X₃ is heterocyclo.

In one preferred embodiment of the present invention, the taxanes of the present invention correspond to structure (2):

wherein

R₇ is hydroxy;

R₁₀ is heterosubstituted acetate;

X₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms;

X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀; and

X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo.

For example, in this preferred embodiment in which the taxane corresponds to structure (2), R₁₀ is R_(10a)COO— wherein R_(10a) is heterosubstituted methyl, more preferably heterosubstituted methyl wherein the heterosubsituents are selected from the group consisting of nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atoms, still more preferably heterosubstituted methyl wherein the heterosubstituent is alkoxy or acyloxy. While R_(10a) is selected from among these, in one embodiment X₃ is selected from substituted or unsubstituted alkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted alkenyl, phenyl or heterocyclo, still more preferably substituted or unsubstituted phenyl or heterocyclo, and still more preferably heterocyclo such as furyl, thienyl or pyridyl. While R_(10a) and X₃ are selected from among these, in one embodiment X₅ is selected from —COX₁₀ wherein X₁₀ is phenyl, alkyl or heterocyclo, more preferably phenyl. Alternatively, while R_(10a) and X₃ are selected from among these, in one embodiment X₅ is selected from —COX₁₀ wherein X₁₀ is phenyl, alkyl or heterocyclo, more preferably phenyl, or X₅ is —COOX₁₀ wherein X₁₀ is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to structure 2 in which (i) X₅ is —COOX₁₀ wherein X₁₀ is tert-butyl or X₅ is —COX₁₀ wherein X₁₀ is phenyl, (ii) X₃ is substituted or unsubstituted cycloalkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted isobutenyl, phenyl, furyl, thienyl, or pyridyl, still more preferably unsubstituted isobutenyl, furyl, thienyl or pyridyl, and (iii) R₁₀ is alkoxyacetyl aryloxyacetyl, or acyloxyacetyl.

Taxanes having the general formula 1 may be obtained by treatment of a b-lactam with an alkoxide having the taxane tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a b-amido ester substituent at C-13 (as described more fully in Holton U.S. Pat. No. 5,466,834), followed by removal of the hydroxy protecting groups. The β-lactam has the following structural formula (3):

wherein P₂ is a hydroxy protecting group and X₃ and X₅ are as previously defined and the alkoxide has the structural formula (4):

wherein M is a metal or ammonium, P₇ is a hydroxy protecting group and R₁₀ is as previously defined. The alkoxide may be prepared from 10-deacetylbaccatin III by selective esterification of the C-10 hydroxyl group and then protection of the C-7 hydroxyl group (as described more fully in Holton et al., PCT Patent Application WO 99/09021) followed by treatment with a metallic amide.

Alternatively, taxanes having the general formula 1 may be obtained by treatment of a b-lactam with an alkoxide having the taxane tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a b-amido ester substituent at C-13 (as described more fully in Holton U.S. Pat. No. 5,466,834), followed by selective deprotection of the C(10) hydroxy group and reaction with an acylating agent such as an alkoxyacetyl halide.

Derivatives of 10-deacetylbaccatin III having alternative substituents at C(2), C(9) and C(14) and processes for their preparation are known in the art. Taxane derivatives having acyloxy substituents other than benzoyloxy at C(2) may be prepared, for example, as described in Holton et al., U.S. Pat. No. 5,728,725 or Kingston et al., U.S. Pat. No. 6,002,023. Taxanes having acyloxy or hydroxy substituents at C(9) in place of keto may be prepared, for example as described in Holton et al., U.S. Pat. No. 6,011,056 or Gunawardana et al., U.S. Pat. No. 5,352,806. Taxanes having a beta hydroxy substituent at C(14) may be prepared from naturally occurring 14-hydroxy-10-deacetylbaccatin III.

Processes for the preparation and resolution of the β-lactam starting material are generally well known. For example, the β-lactam may be prepared as described in Holton, U.S. Pat. No. 5,430,160 and the resulting enatiomeric mixtures of β-lactams may be resolved by a stereoselective hydrolysis using a lipase or enzyme as described, for example, in Patel, U.S. Pat. No. 5,879,929 Patel U.S. Pat. No. 5,567,614 or a liver homogenate as described, for example, in PCT Patent Application No. 00/41204. In a preferred embodiment in which the β-lactam is furyl substituted at the C(4) position, the β-lactam can be prepared as illustrated in the following reaction scheme:

wherein Ac is acetyl, NEt₃ is triethylamine, CAN is ceric ammonium nitrate, and p-TsOH is p-toluenesulfonic acid. The beef liver resolution may be carried out, for example, by combining the enatiomeric β-lactam mixture with a beef liver suspension (prepared, for example, by adding 20 g of frozen beef liver to a blender and then adding a pH 8 buffer to make a total volume of 1 L).

Compounds of formula 1 of the instant invention are useful for inhibiting tumor growth in mammals including humans and are preferably administered in the form of a pharmaceutical composition comprising an effective antitumor amount of a compound of the instant invention in combination with at least one pharmaceutically or pharmacologically acceptable carrier. The carrier, also known in the art as an excipient, vehicle, auxiliary, adjuvant, or diluent, is any substance which is pharmaceutically inert, confers a suitable consistency or form to the composition, and does not diminish the therapeutic efficacy of the antitumor compounds. The carrier is “pharmaceutically or pharmacologically acceptable” if it does not produce an adverse, allergic or other untoward reaction when administered to a mammal or human, as appropriate.

The pharmaceutical compositions containing the antitumor compounds of the present invention may be formulated in any conventional manner. Proper formulation is dependent upon the route of administration chosen. The compositions of the invention can be formulated for any route of administration so long as the target tissue is available via that route. Suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous; intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal), topical (nasal, transdermal, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratracheal, intralesional, percutaneous, endoscopical, transmucosal, sublingual and intestinal administration.

Pharmaceutically acceptable carriers for use in the compositions of the present invention are well known to those of ordinary skill in the art and are selected based upon a number of factors: the particular antitumor compound used, and its concentration, stability and intended bioavailability; the disease, disorder or condition being treated with the composition; the subject, its age, size and general condition; and the route of administration. Suitable carriers are readily determined by one of ordinary skill in the art (see, for example, J. G. Nairn, in: Remington's Pharmaceutical Science (A. Gennaro, ed.), Mack Publishing Co., Easton, Pa., (1985), pp. 1492–1517, the contents of which are incorporated herein by reference).

The compositions are preferably formulated as tablets, dispersible powders, pills, capsules, gelcaps, caplets, gels, liposomes, granules, solutions, suspensions, emulsions, syrups, elixirs, troches, dragees, lozenges, or any other dosage form which can be administered orally. Techniques and compositions for making oral dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).

The compositions of the invention for oral administration comprise an effective antitumor amount of a compound of the invention in a pharmaceutically acceptable carrier. Suitable carriers for solid dosage forms include sugars, starches, and other conventional substances including lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, corn starch, potato starch, sodium saccharin, magnesium carbonate, tragacanth, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, and stearic acid. Further, such solid dosage forms may be uncoated or may be coated by known techniques; e.g., to delay disintegration and absorption.

The antitumor compounds of the present invention are also preferably formulated for parenteral administration, e.g., formulated for injection via intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal routes. The compositions of the invention for parenteral administration comprise an effective antitumor amount of the antitumor compound in a pharmaceutically acceptable carrier. Dosage forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions or any other dosage form which can be administered parenterally. Techniques and compositions for making parenteral dosage forms are known in the art.

Suitable carriers used in formulating liquid dosage forms for oral or parenteral administration include nonaqueous, pharmaceutically-acceptable polar solvents such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, as well as water, saline solutions, dextrose solutions (e.g., DW5), electrolyte solutions, or any other aqueous, pharmaceutically acceptable liquid.

Suitable nonaqueous, pharmaceutically-acceptable polar solvents include, but are not limited to, alcohols (e.g., α-glycerol formal, β-glycerol formal, 1,3-butyleneglycol, aliphatic or aromatic alcohols having 2–30 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fatty alcohols such as polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g., dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide, N-(β-hydroxyethyl)-lactamide, N,N-dimethylacetamide-amides, 2-pyrrolidinone, 1-methyl-2-pyrrolidinone, or polyvinylpyrrolidone); esters (e.g., 1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetate esters such as monoacetin, diacetin, and triacetin, aliphatic or aromatic esters such as ethyl caprylate or octanoate, alkyl oleate, benzyl benzoate, benzyl acetate, dimethylsulfoxide (DMSO), esters of glycerin such as mono, di, or tri-glyceryl citrates or tartrates, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan, fatty acid derived PEG esters, glyceryl monostearate, glyceride esters such as mono, di, or tri-glycerides, fatty acid esters such as isopropyl myristrate, fatty acid derived PEG esters such as PEG-hydroxyoleate and PEG-hydroxystearate, N-methylpyrrolidinone, pluronic 60, polyoxyethylene sorbitol oleic polyesters such as poly(ethoxylated)₃₀₋₆₀ sorbitol poly(oleate)₂₋₄, poly(oxyethylene)₁₅₋₂₀ monooleate, poly(oxyethylene)₁₅₋₂₀ mono 12-hydroxystearate, and poly(oxyethylene)₁₅₋₂₀ mono ricinoleate, polyoxyethylene sorbitan esters such as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitan monopalmitate, polyoxyethylene-sorbitan monolaurate, polyoxyethylene-sorbitan monostearate, and Polysorbate® 20, 40, 60 or 80 from ICI Americas, Wilmington, Del., polyvinylpyrrolidone, alkyleneoxy modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor® RH 40 solution), saccharide fatty acid esters (i.e., the condensation product of a monosaccharide (e.g., pentoses such as ribose, ribulose, arabinose, xylose, lyxose and xylulose, hexoses such as glucose, fructose, galactose, mannose and sorbose, trioses, tetroses, heptoses, and octoses), disaccharide (e.g., sucrose, maltose, lactose and trehalose) or oligosaccharide or mixture thereof with a C₄-C₂₂ fatty acid(s)(e.g., saturated fatty acids such as caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid, and unsaturated fatty acids such as palmitoleic acid, oleic acid, elaidic acid, erucic acid and linoleic acid)), or steroidal esters); alkyl, aryl, or cyclic ethers having 2–30 carbon atoms (e.g., diethyl ether, tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethyl ether); glycofurol (tetrahydrofurfuryl alcohol polyethylene glycol ether); ketones having 3–30 carbon atoms (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatic hydrocarbons having 4–30 carbon atoms (e.g., benzene, cyclohexane, dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane, sulfolane, tetramethylenesulfon, tetramethylenesulfoxide, toluene, dimethylsulfoxide (DMSO), or tetramethylenesulfoxide); oils of mineral, vegetable, animal, essential or synthetic origin (e.g., mineral oils such as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic based hydrocarbons, and refined paraffin oil, vegetable oils such as linseed, tung, safflower, soybean, castor, cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn germ, sesame, persic and peanut oil and glycerides such as mono-, di- or triglycerides, animal oils such as fish, marine, sperm, cod-liver, haliver, squalene, squalane, and shark liver oil, oleic oils, and polyoxyethylated castor oil); alkyl or aryl halides having 1–30 carbon atoms and optionally more than one halogen substituent; methylene chloride; monoethanolamine; petroleum benzin; trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid); polyglycol ester of 12-hydroxystearic acid and polyethylene glycol (Solutol® HS-15, from BASF, Ludwigshafen, Germany); polyoxyethylene glycerol; sodium laurate; sodium oleate; or sorbitan monooleate.

Other pharmaceutically acceptable solvents for use in the invention are well known to those of ordinary skill in the art, and are identified in The Chemotherapy Source Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipients, (American Pharmaceutical Association, Washington, D.C., and The Pharmaceutical Society of Great Britain, London, England, 1968), Modern Pharmaceutics, (G. Banker et al., eds., 3d ed.)(Marcel Dekker, Inc., New York, N.Y., 1995), The Pharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw Hill Publishing), Pharmaceutical Dosage Forms, (H. Lieberman et al., eds.,)(Marcel Dekker, Inc., New York, N.Y., 1980), Remington's Pharmaceutical Sciences (A. Gennaro, ed., 19th ed.)(Mack Publishing, Easton, Pa., 1995), The United States Pharmacopeia 24, The National Formulary 19, (National Publishing, Philadelphia, Pa., 2000), A. J. Spiegel et al., and Use of Nonaqueous Solvents in Parenteral Products, JOURNAL OF PHARMACEUTICAL SCIENCES, Vol. 52, No. 10, pp. 917–927 (1963).

Preferred solvents include those known to stabilize the antitumor compounds, such as oils rich in triglycerides, for example, safflower oil, soybean oil or mixtures thereof, and alkyleneoxy modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor® RH 40 solution). Commercially available triglycerides include Intralipid® emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm, Sweden), Nutralipid® emulsion (McGaw, Irvine, Calif.), Liposyn® II 20% emulsion (a 20% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, Ill.), Liposyn® III 2% emulsion (a 2% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, Ill.), natural or synthetic glycerol derivatives containing the docosahexaenoyl group at levels between 25% and 100% by weight based on the total fatty acid content (Dhasco® (from Martek Biosciences Corp., Columbia, Md.), DHA Maguro® (from Daito Enterprises, Los Angeles, Calif.), Soyacal®, and Travemulsion®. Ethanol is a preferred solvent for use in dissolving the antitumor compound to form solutions, emulsions, and the like.

Additional minor components can be included in the compositions of the invention for a variety of purposes well known in the pharmaceutical industry. These components will for the most part impart properties which enhance retention of the antitumor compound at the site of administration, protect the stability of the composition, control the pH, facilitate processing of the antitumor compound into pharmaceutical formulations, and the like. Preferably, each of these components is individually present in less than about 15 weight % of the total composition, more preferably less than about 5 weight %, and most preferably less than about 0.5 weight % of the total composition. Some components, such as fillers or diluents, can constitute up to 90 wt. % of the total composition, as is well known in the formulation art. Such additives include cryoprotective agents for preventing reprecipitation of the taxane, surface active, wetting or emulsifying agents (e.g., lecithin, polysorbate-80, Tween® 80, pluronic 60, polyoxyethylene stearate), preservatives (e.g., ethyl-p-hydroxybenzoate), microbial preservatives (e.g., benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben), agents for adjusting pH or buffering agents (e.g., acids, bases, sodium acetate, sorbitan monolaurate), agents for adjusting osmolarity (e.g., glycerin), thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose, tristearin, cetyl wax esters, polyethylene glycol), colorants, dyes, flow aids, non-volatile silicones (e.g., cyclomethicone), clays (e.g., bentonites), adhesives, bulking agents, flavorings, sweeteners, adsorbents, fillers (e.g., sugars such as lactose, sucrose, mannitol, or sorbitol, cellulose, or calcium phosphate), diluents (e.g., water, saline, electrolyte solutions), binders (e.g., starches such as maize starch, wheat starch, rice starch, or potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, sugars, polymers, acacia), disintegrating agents (e.g., starches such as maize starch, wheat starch, rice starch, potato starch, or carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate, croscarmellose sodium or crospovidone), lubricants (e.g., silica, talc, stearic acid or salts thereof such as magnesium stearate, or polyethylene glycol), coating agents (e.g., concentrated sugar solutions including gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide), and antioxidants (e.g., sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose, phenols, and thiophenols).

In a preferred embodiment, a pharmaceutical composition of the invention comprises at least one nonaqueous, pharmaceutically acceptable solvent and an antitumor compound having a solubility in ethanol of at least about 100, 200, 300, 400, 500, 600, 700 or 800 mg/ml. While not being bound to a particular theory, it is believed that the ethanol solubility of the antitumor compound may be directly related to its efficacy. The antitumor compound can also be capable of being crystallized from a solution. In other words, a crystalline antitumor compound, such as compound 1393, can be dissolved in a solvent to form a solution and then recrystallized upon evaporation of the solvent without the formation of any amorphous antitumor compound. It is also preferred that the antitumor compound have an ID50 value (i.e, the drug concentration producing 50% inhibition of colony formation) of at least 4, 5, 6, 7, 8, 9, or 10 times less that of paclitaxel when measured according to the protocol set forth in the working examples.

Dosage form administration by these routes may be continuous or intermittent, depending, for example, upon the patient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to and assessable by a skilled practitioner.

Dosage and regimens for the administration of the pharmaceutical compositions of the invention can be readily determined by those with ordinary skill in treating cancer. It is understood that the dosage of the antitumor compounds will be dependent upon the age, sex, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. For any mode of administration, the actual amount of antitumor compound delivered, as well as the dosing schedule necessary to achieve the advantageous effects described herein, will also depend, in part, on such factors as the bioavailability of the antitumor compound, the disorder being treated, the desired therapeutic dose, and other factors that will be apparent to those of skill in the art. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect the desired therapeutic response in the animal over a reasonable period of time. Preferably, an effective amount of the antitumor compound, whether administered orally or by another route, is any amount which would result in a desired therapeutic response when administered by that route. Preferably, the compositions for oral administration are prepared in such a way that a single dose in one or more oral preparations contains at least 20 mg of the antitumor compound per m² Of patient body surface area, or at least 50, 100, 150, 200, 300, 400, or 500 mg of the antitumor compound per m² of patient body surface area, wherein the average body surface area for a human is 1.8 m². Preferably, a single dose of a composition for oral administration contains from about 20 to about 600 mg of the antitumor compound per m² of patient body surface area, more preferably from about 25 to about 400 mg/m², even more preferably, from about 40 to about 300 mg/m², and even more preferably from about 50 to about 200 mg/m². Preferably, the compositions for parenteral administration are prepared in such a way that a single dose contains at least 20 mg of the antitumor compound per m² of patient body surface area, or at least 40, 50, 100, 150, 200, 300, 400, or 500 mg of the antitumor compound per m² of patient body surface area. Preferably, a single dose in one or more parenteral preparations contains from about 20 to about 500 mg of the antitumor compound per m² of patient body surface area, more preferably from about 40 to about 400 mg/m², and even more preferably, from about 60 to about 350 mg/m². However, the dosage may vary depending on the dosing schedule which can be adjusted as necessary to achieve the desired therapeutic effect. It should be noted that the ranges of effective doses provided herein are not intended to limit the invention and represent preferred dose ranges. The most preferred dosage will be tailored to the individual subject, as is understood and determinable by one of ordinary skill in the art without undue experimentation.

The concentration of the antitumor compound in a liquid pharmaceutical composition is preferably between about 0.01 mg and about 10 mg per ml of the composition, more preferably between about 0.1 mg and about 7 mg per ml, even more preferably between about 0.5 mg and about 5 mg per ml, and most preferably between about 1.5 mg and about 4 mg per ml. Relatively low concentrations are generally preferred because the antitumor compound is most soluble in the solution at low concentrations. The concentration of the antitumor compound in a solid pharmaceutical composition for oral administration is preferably between about 5 weight % and about 50 weight 0%, based on the total weight of the composition, more preferably between about 8 weight % and about 40 weight %, and most preferably between about 10 weight % and about 30 weight %.

In one embodiment, solutions for oral administration are prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. An appropriate volume of a carrier which is a solution, such as Cremophor® EL solution, is added to the solution while stirring to form a pharmaceutically acceptable solution for oral administration to a patient. If desired, such solutions can be formulated to contain a minimal amount of, or to be free of, ethanol, which is known in the art to cause adverse physiological effects when administered at certain concentrations in oral formulations.

In another embodiment, powders or tablets for oral administration are prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. The solvent can optionally be capable of evaporating when the solution is dried under vacuum. An additional carrier can be added to the solution prior to drying, such as Cremophor® EL solution. The resulting solution is dried under vacuum to form a glass. The glass is then mixed with a binder to form a powder. The powder can be mixed with fillers or other conventional tabletting agents and processed to form a tablet for oral administration to a patient. The powder can also be added to any liquid carrier as described above to form a solution, emulsion, suspension or the like for oral administration.

Emulsions for parenteral administration can be prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. An appropriate volume of a carrier which is an emulsion, such as Liposyn® II or Liposyn® III emulsion, is added to the solution while stirring to form a pharmaceutically acceptable emulsion for parenteral administration to a patient. If desired, such emulsions can be formulated to contain a minimal amount of, or to be free of, ethanol or Cremophor® solution, which are known in the art to cause adverse physiological effects when administered at certain concentrations in parenteral formulations.

Solutions for parenteral administration can be prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. An appropriate volume of a carrier which is a solution, such as Cremophor® solution, is added to the solution while stirring to form a pharmaceutically acceptable solution for parenteral administration to a patient. If desired, such solutions can be formulated to contain a minimal amount of, or to be free of, ethanol or Cremophor® solution, which are known in the art to cause adverse physiological effects when administered at certain concentrations in parenteral formulations.

If desired, the emulsions or solutions described above for oral or parenteral administration can be packaged in IV bags, vials or other conventional containers in concentrated form and diluted with any pharmaceutically acceptable liquid, such as saline, to form an acceptable taxane concentration prior to use as is known in the art.

Definitions

The terms “hydrocarbon” and “hydrocarbyl” as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms.

The “substituted hydrocarbyl” moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom. These substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketals, acetals, esters and ethers.

The term “heteroatom” shall mean atoms other than carbon and hydrogen.

The “heterosubstituted methyl” moieties described herein are methyl groups in which the carbon atom is covalently bonded to at least one heteroatom and optionally with hydrogen, the heteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatom may, in turn, be substituted with other atoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety.

The “heterosubstituted acetate” moieties described herein are acetate groups in which the carbon of the methyl group is covalently bonded to at least one heteroatom and optionally with hydrogen, the heteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatom may, in turn, be substituted with other atoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety.

Unless otherwise indicated, the alkyl groups described herein are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like.

Unless otherwise indicated, the alkenyl groups described herein are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.

Unless otherwise indicated, the alkynyl groups described herein are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.

The terms “aryl” or “ar” as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the more preferred aryl.

The terms “halogen” or “halo” as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.

The terms “heterocyclo” or “heterocyclic” as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or nonaromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heterocyclo include heteroaromatics such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.

The term “heteroaromatic” as used herein alone or as part of another group denote optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heteroaromatics include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.

The term “acyl,” as used herein alone or as part of another group, denotes the moiety formed by removal of the hydroxyl group from the group —COOH of an organic carboxylic acid, e.g., RC(O)—, wherein R is R¹, R¹O—, R¹R²N—, or R¹S—, R¹ is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo and R² is hydrogen, hydrocarbyl or substituted hydrocarbyl.

The term “acyloxy,” as used herein alone or as part of another group, denotes an acyl group as described above bonded through an oxygen linkage (—O—), e.g., RC(O)O— wherein R is as defined in connection with the term “acyl.”

Unless otherwise indicated, the alkoxycarbonyloxy moieties described herein comprise lower hydrocarbon or substituted hydrocarbon or substituted hydrocarbon moieties.

Unless otherwise indicated, the carbamoyloxy moieties described herein are derivatives of carbamic acid in which one or both of the amine hydrogens is optionally replaced by a hydrocarbyl, substituted hydrocarbyl or heterocyclo moiety.

The terms “hydroxyl protecting group” and “hydroxy protecting group” as used herein denote a group capable of protecting a free hydroxyl group (“protected hydroxyl”) which, subsequent to the reaction for which protection is employed, may be removed without disturbing the remainder of the molecule. A variety of protecting groups for the hydroxyl group and the synthesis thereof may be found in “Protective Groups in Organic Synthesis” by T. W. Greene, John Wiley and Sons, 1981, or Fieser & Fieser. Exemplary hydroxyl protecting groups include methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (.beta.-trimethylsilylethoxy)methyl, tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl, t-butyl(diphenyl)silyl, trialkylsilyl, trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl.

As used herein, “Ac” means acetyl; “Bz” means benzoyl; “Et” means ethyl; “Me” means methyl; “Ph” means phenyl; “iPr” means isopropyl; “tBu” and “t-Bu” means tert-butyl; “R” means lower alkyl unless otherwise defined; “py” means pyridine or pyridyl; “TES” means triethylsilyl; “TMS” means trimethylsilyl; “LAH” means lithium aluminum hydride; “10-DAB” means 10-desacetylbaccatin III”; “amine protecting group” includes, but is not limited to, carbamates, for example, 2,2,2-trichloroethylcarbamate or tertbutylcarbamate; “protected hydroxy” means —OP wherein P is a hydroxy protecting group; “tBuOCO” means tert-butoxycarbonyl; “tAmOCO” means tert-amyloxycarbonyl; “PhCO means phenylcarbonyl”; “2-FuCO” means 2-furylcarbonyl; “2-ThCO” means 2-thienylcarbonyl; “2-PyCO” means 2-pyridylcarbonyl; “3-PyCO” means 3-pyridylcarbonyl; “4-PyCO” means 4-pyridylcarbonyl; “C₄H₇CO” means butenylcarbonyl; “EtOCO” means ethoxycarbonyl; “ibueCO” means isobutenylcarbonyl; “iBuCO” means isobutylcarbonyl; “iBuOCO” means isobutoxycarbonyl; “iPrOCO” means isopropyloxycarbonyl; “nPrOCO” means n-propyloxycarbonyl; “nPrCO” means n-propylcarbonyl; “tC₃H₅CO” means trans-propenyl carbonyl; “ibue” means isobutenyl; “THF” means tetrahydrofuran; “DMAP” means 4-dimethylamino pyridine; and “LHMDS” means lithium hexamethyl disilazanide.

The following examples illustrate the invention.

EXAMPLE 1 N-Debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-10-methoxyacetyl Taxol (6515)

To a solution of N-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-2′-(2-methoxy-2-propyl)-7-benzyloxycarbonyl-10-deacetyl-10-trimethylsilyl taxol (3.50 g) in 40 mL of 1:1 acetonitrile-pyridine at 0° C. (ice-water bath) was added dropwise over 10 minutes, 10 mL of 48% aqueous hydrofluoric acid. The cooling bath was then removed and the reaction stirred at ambient temperature for 8 h, diluted with 200 mL of ethyl acetate and washed with 25 mL of water, 2×20 mL of saturated aqueous NaHCO₃ and 25 mL of saturated aqueous NaCl. The organic layer was then dried over sodium sulfate and concentrated under reduced pressure to give N-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-7-benzyloxy-arbonyl-10-deacetyl taxol as a white solid which was dried under high vacuum (0.1 mmHg, 12 h) and used directly in the next step.

To a solution of N-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-7-benzyloxycarbonyl-10-deacetyl taxol (2.17 g, 2.293 mmol) in anhydrous methylene chloride (6 mL) was added with stirring triethylamine (1.60 mL, 11.46 mmol) followed by the dropwise addition of 0.46 mL of triethylsilyl chloride. TLC of the mixture (silica gel, 2:3 ethyl acetate:hexane) after 2 h, showed the formation of only one product. Saturated aqueous NaHCO₃, 2 mL was added to the reaction which was then diluted with 70 mL of ethyl acetate, washed with 10 mL of saturated aqueous NaHCO₃ and 15 mL of saturated aqueous NaCl. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give pure N-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-2′-triethylsilyl-7-benzyloxycarbonyl-10deacetyl taxol as a white solid (2.21 g, 91%).

To a solution of N-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-2′-triethylsilyl-7-benzyloxycarbonyl-10-deacetyl taxol (660 mg, 0.622 mmol) in 4 mL anhydrous pyridine at 0° C. was added DMAP (20 mg, 0.16 mmol) under a nitrogen atmosphere. To this mixture was added drop wise methoxyacetyl chloride (220 mL, 2.489 mmol). TLC (silica gel, 2:3 ethyl acetate:hexane) after 2 h showed no starting material. The reaction was cooled to 0° C. (ice-water bath) and quenched by adding 80 mL of water.

To the reaction at 0° C. (ice-water bath) was added 4 mL of acetonitrile and 2 mL of 48% aqueous hydrofluoric acid and the cooling bath was removed. The reaction was stirred at room temperature for 8.0 h, diluted with 60 mL of ethyl acetate and washed with 10 mL of saturated aqueous NaHCO₃ and 15 mL of saturated aqueous NaCl. The organic layer was dried over Na₂SO₄ and concentrated under reduce pressure to give 602 mg of a yellow solid which was purified by flash-chromatography (silica gel, 1:1 ethyl acetate:hexane) to give 538 mg (85%) of pure N-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-7-benzyloxycarbonyl-10-deacetyl-10-methoxyacetyl taxol (TL-650): mp 145–146° C.; Anal. Calcd. for C₅₃H₆₃NO₁₉: C, 62.53; H, 6.24. Found: C, 62.26; H, 6.20.

To a solution of N-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-7-benzyloxycarbonyl-10-deacetyl-10-methoxyacetyl taxol (TL-650, 350 mg, 0.343 mmol) in 15 mL ethyl acetate was added 10% Pd—C (100 mg). The mixture was stirred under a H₂ atmosphere (using latex balloons) for 1 h, when TLC (silica gel, 1:1 ethyl acetate:hexane) showed no starting material. The reaction was then filtered through celite (3 g) and the celite pad washed with 25 mL of ethyl acetate. The combined organic extract was concentrated under reduced pressure to give 315 mg of a white solid which was purified by flash-chromatography (silica gel, 55:45 ethyl acetate:hexane) to give 283 mg (93%) of pure N-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)- -10-deacetyl-10-methoxyacetyl taxol: mp 164–166° C.; ¹H NMR (CDCl₃) 8.13 (m, 2H), 7.62 (m, 1H), 7.46–7.51 (m, 2H), 7.41 (m, 1H), 6.41 (bs, 1H), 6.39 (dd, J=3.1, 1.5 Hz, 1H), 6.25 (d, J=3.1 Hz, 1H), 6.22 (dd, J=8.8, 8.7 Hz, 1H), 5.67 (1H), 5.22–5.38 (m, 2H), 4.98 (m, 1H), 4.76 (m, 1H), 4.42 (m, 2H), 4.36 (d, J=9.3 Hz, 1H), 4.28 (m, 1H), 4.21 (d, J=9.3 Hz, 1H), 3.82 (m, 1H), 3.42 (s, 3H), 3.41 (d, J=5.5 Hz, 1H), 2.55–2.60 (m, 1H), 2.41 (s, 3H), 2.20–2.38 (m, 2H), 1.92 (s, 3H), 1.91–1.94 (m, 1H), 1.68 (bs, 3H), 1.62–1.68 (m, 2H), 1.62 (S, 3H), 1.36 (s, 3H), 1.34 (s, 3H), 1.23 (s, 3H), 1.16 (s, 3H), 0.80 (t, J=8.2 Hz, 3H); Anal. Calcd. for C₄₅H₅₇NO₁₇.½H₂O: C, 60.47; H, 6.49. Found: C, 60.64; H, 6.45.

EXAMPLE 2

The procedures described in Example 1 were repeated, but other suitably protected β-lactams were substituted for the β-lactam of Example 1 to prepare the series of compounds having structural formula (13) and the combinations of substituents identified in the following table

(13)

Compound X₅ X₃ R₁₀ 6577 tAmOCO 2-furyl AcOAcO— 6515 tAmOCO 2-furyl MeOAcO— 6066 tC₃H₅CO 2-furyl MeOAcO— 6111 tC₃H₅CO 2-furyl PhOAcO—

EXAMPLE 3

Following the processes described in Example 1 and elsewhere herein, the following specifictaxanes having structural formula 14 may be prepared, wherein R₁₀ is R_(10a)COO— and R_(10a) is heterosubstituted methyl. In one embodiment, R_(10a) is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, phenoxymethyl, acetoxymethyl, acyloxymethyl, or methylthiomethyl.

(14)

X₅ X₃ R₁₀ tBuOCO— 2-furyl R_(10a)COO— tBuOCO— 3-furyl R_(10a)COO— tBuOCO— 2-thienyl R_(10a)COO— tBuOCO— 3-thienyl R_(10a)COO— tBuOCO— 2-pyridyl R_(10a)COO— tBuOCO— 3-pyridyl R_(10a)COO— tBuOCO— 4-pyridyl R_(10a)COO— tBuOCO— isobutenyl R_(10a)COO— tBuOCO— isopropyl R_(10a)COO— tBuOCO— cyclopropyl R_(10a)COO— tBuOCO— cyclobutyl R_(10a)COO— tBuOCO— cyclopentyl R_(10a)COO— tBuOCO— phenyl R_(10a)COO— benzoyl 2-furyl R_(10a)COO— benzoyl 3-furyl R_(10a)COO— benzoyl 2-thienyl R_(10a)COO— benzoyl 3-thienyl R_(10a)COO— benzoyl 2-pyridyl R_(10a)COO— benzoyl 3-pyridyl R_(10a)COO— benzoyl 4-pyridyl R_(10a)COO— benzoyl isobutenyl R_(10a)COO— benzoyl isopropyl R_(10a)COO— benzoyl cyclopropyl R_(10a)COO— benzoyl cyclobutyl R_(10a)COO— benzoyl cyclopentyl R_(10a)COO— benzoyl phenyl R_(10a)COO— 2-FuCO— 2-furyl R_(10a)COO— 2-FuCO— 3-furyl R_(10a)COO— 2-FuCO— 2-thienyl R_(10a)COO— 2-FuCO— 3-thienyl R_(10a)COO— 2-FuCO— 2-pyridyl R_(10a)COO— 2-FuCO— 3-pyridyl R_(10a)COO— 2-FuCO— 4-pyridyl R_(10a)COO— 2-FuCO— isobutenyl R_(10a)COO— 2-FuCO— isopropyl R_(10a)COO— 2-FuCO— cyclopropyl R_(10a)COO— 2-FuCO— cyclobutyl R_(10a)COO— 2-FuCO— cyclopentyl R_(10a)COO— 2-FuCO— phenyl R_(10a)COO— 2-ThCO— 2-furyl R_(10a)COO— 2-ThCO— 3-furyl R_(10a)COO— 2-ThCO— 2-thienyl R_(10a)COO— 2-ThCO— 3-thienyl R_(10a)COO— 2-ThCO— 2-pyridyl R_(10a)COO— 2-ThCO— 3-pyridyl R_(10a)COO— 2-ThCO— 4-pyridyl R_(10a)COO— 2-ThCO— isobutenyl R_(10a)COO— 2-ThCO— isopropyl R_(10a)COO— 2-ThCO— cyclopropyl R_(10a)COO— 2-ThCO— cyclobutyl R_(10a)COO— 2-ThCO— cyclopentyl R_(10a)COO— 2-ThCO— phenyl R_(10a)COO— 2-PyCO— 2-furyl R_(10a)COO— 2-PyCO— 3-furyl R_(10a)COO— 2-PyCO— 2-thienyl R_(10a)COO— 2-PyCO— 3-thienyl R_(10a)COO— 2-PyCO— 2-pyridyl R_(10a)COO— 2-PyCO— 3-pyridyl R_(10a)COO— 2-PyCO— 4-pyridyl R_(10a)COO— 2-PyCO— isobutenyl R_(10a)COO— 2-PyCO— isopropyl R_(10a)COO— 2-PyCO— cyclopropyl R_(10a)COO— 2-PyCO— cyclobutyl R_(10a)COO— 2-PyCO— cyclopentyl R_(10a)COO— 2-PyCO— phenyl R_(10a)COO— 3-PyCO— 2-furyl R_(10a)COO— 3-PyCO— 3-furyl R_(10a)COO— 3-PyCO— 2-thienyl R_(10a)COO— 3-PyCO— 3-thienyl R_(10a)COO— 3-PyCO— 2-pyridyl R_(10a)COO— 3-PyCO— 3-pyridyl R_(10a)COO— 3-PyCO— 4-pyridyl R_(10a)COO— 3-PyCO— isobutenyl R_(10a)COO— 3-PyCO— isopropyl R_(10a)COO— 3-PyCO— cyclopropyl R_(10a)COO— 3-PyCO— cyclobutyl R_(10a)COO— 3-PyCO— cyclopentyl R_(10a)COO— 3-PyCO— phenyl R_(10a)COO— 4-PyCO— 2-furyl R_(10a)COO— 4-PyCO— 3-furyl R_(10a)COO— 4-PyCO— 2-thienyl R_(10a)COO— 4-PyCO— 3-thienyl R_(10a)COO— 4-PyCO— 2-pyridyl R_(10a)COO— 4-PyCO— 3-pyridyl R_(10a)COO— 4-PyCO— 4-pyridyl R_(10a)COO— 4-PyCO— isobutenyl R_(10a)COO— 4-PyCO— isopropyl R_(10a)COO— 4-PyCO— cyclopropyl R_(10a)COO— 4-PyCO— cyclobutyl R_(10a)COO— 4-PyCO— cyclopentyl R_(10a)COO— 4-PyCO— phenyl R_(10a)COO— C₄H₇CO— 2-furyl R_(10a)COO— C₄H₇CO— 3-furyl R_(10a)COO— C₄H₇CO— 2-thienyl R_(10a)COO— C₄H₇CO— 3-thienyl R_(10a)COO— C₄H₇CO— 2-pyridyl R_(10a)COO— C₄H₇CO— 3-pyridyl R_(10a)COO— C₄H₇CO— 4-pyridyl R_(10a)COO— C₄H₇CO— isobutenyl R_(10a)COO— C₄H₇CO— isopropyl R_(10a)COO— C₄H₇CO— cyclopropyl R_(10a)COO— C₄H₇CO— cyclobutyl R_(10a)COO— C₄H₇CO— cyclopentyl R_(10a)COO— C₄H₇CO— phenyl R_(10a)COO— EtOCO— 2-furyl R_(10a)COO— EtOCO— 3-furyl R_(10a)COO— EtOCO— 2-thienyl R_(10a)COO— EtOCO— 3-thienyl R_(10a)COO— EtOCO— 2-pyridyl R_(10a)COO— EtOCO— 3-pyridyl R_(10a)COO— EtOCO— 4-pyridyl R_(10a)COO— EtOCO— isobutenyl R_(10a)COO— EtOCO— isopropyl R_(10a)COO— EtOCO— cyclopropyl R_(10a)COO— EtOCO— cyclobutyl R_(10a)COO— EtOCO— cyclopentyl R_(10a)COO— EtOCO— phenyl R_(10a)COO— ibueCO— 2-furyl R_(10a)COO— ibueCO— 3-furyl R_(10a)COO— ibueCO— 2-thienyl R_(10a)COO— ibueCO— 3-thienyl R_(10a)COO— ibueCO— 2-pyridyl R_(10a)COO— ibueCO— 3-pyridyl R_(10a)COO— ibueCO— 4-pyridyl R_(10a)COO— ibueCO— isobutenyl R_(10a)COO— ibueCO— isopropyl R_(10a)COO— ibueCO— cyclopropyl R_(10a)COO— ibueCO— cyclobutyl R_(10a)COO— ibueCO— cyclopentyl R_(10a)COO— ibueCO— phenyl R_(10a)COO— iBuCO— 2-furyl R_(10a)COO— iBuCO— 3-furyl R_(10a)COO— iBuCO— 2-thienyl R_(10a)COO— iBuCO— 3-thienyl R_(10a)COO— iBuCO— 2-pyridyl R_(10a)COO— iBuCO— 3-pyridyl R_(10a)COO— iBuCO— 4-pyridyl R_(10a)COO— iBuCO— isobutenyl R_(10a)COO— iBuCO— isopropyl R_(10a)COO— iBuCO— cyclopropyl R_(10a)COO— IBuCO— cyclobutyl R_(10a)COO— iBuCO— cyclopentyl R_(10a)COO— iBuCO— phenyl R_(10a)COO— iBuOCO— 2-furyl R_(10a)COO— iBuOCO— 3-furyl R_(10a)COO— iBuOCO— 2-thienyl R_(10a)COO— iBuOCO— 3-thienyl R_(10a)COO— iBuOCO— 2-pyridyl R_(10a)COO— iBuOCO— 3-pyridyl R_(10a)COO— iBuOCO— 4-pyridyl R_(10a)COO— iBuOCO— isobutenyl R_(10a)COO— iBuOCO— isopropyl R_(10a)COO— iBuOCO— cyclopropyl R_(10a)COO— iBuOCO— cyclobutyl R_(10a)COO— iBuOCO— cyclopentyl R_(10a)COO— iBuOCO— phenyl R_(10a)COO— iPrOCO— 2-furyl R_(10a)COO— iPrOCO— 3-furyl R_(10a)COO— iPrOCO— 2-thienyl R_(10a)COO— iPrOCO— 3-thienyl R_(10a)COO— iPrOCO— 2-pyridyl R_(10a)COO— IPrOCO— 3-pyridyl R_(10a)COO— iPrOCO— 4-pyridyl R_(10a)COO— iPrOCO— isobutenyl R_(10a)COO— iPrOCO— isopropyl R_(10a)COO— iPrOCO— cyclopropyl R_(10a)COO— iPrOCO— cyclobutyl R_(10a)COO— iPrOCO— cyclopentyl R_(10a)COO— iPrOCO— phenyl R_(10a)COO— nPrOCO— 2-furyl R_(10a)COO— nPrOCO— 3-furyl R_(10a)COO— nPrOCO— 2-thienyl R_(10a)COO— nPrOCO— 3-thienyl R_(10a)COO— nPrOCO— 2-pyridyl R_(10a)COO— nPrOCO— 3-pyridyl R_(10a)COO— nPrOCO— 4-pyridyl R_(10a)COO— nPrOCO— isobutenyl R_(10a)COO— nPrOCO— isopropyl R_(10a)COO— nPrOCO— cyclopropyl R_(10a)COO— nPrOCO— cyclobutyl R_(10a)COO— nPrOCO— cyclopentyl R_(10a)COO— nPrOCO— phenyl R_(10a)COO— nPrCO— 2-furyl R_(10a)COO— nPrCO— 3-furyl R_(10a)COO— nPrCO— 2-thienyl R_(10a)COO— nPrCO— 3-thienyl R_(10a)COO— nPrCO— 2-pyridyl R_(10a)COO— nPrCO— 3-pyridyl R_(10a)COO— nPrCO— 4-pyridyl R_(10a)COO— nPrCO— isobutenyl R_(10a)COO— nPrCO— isopropyl R_(10a)COO— nPrCO— cyclopropyl R_(10a)COO— nPrCO— cyclobutyl R_(10a)COO— nPrCO— cyclopentyl R_(10a)COO— nPrCO— phenyl R_(10a)COO—

EXAMPLE 4

Following the processes described in Example 1 and elsewhere herein, the following specific taxanes having structural formula 15 may be prepared, wherein R₇ is hydroxy and R₁₀ in each of the series (that is, each of series “A” through “K”) is as previously defined, including wherein R₁₀ is R_(10a)COO— wherein R_(10a) is a heterosubstituted methyl moiety lacking a carbon atom which is in the beta position relative to the carbon atom of which R_(10a) is a substituent. The heterosubstituted methyl is covalently bonded to at least one heteroatom and optionally with hydrogen, the heteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatom may, in turn, be substituted with other atoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety. Exemplary R₁₀ substituents include R_(10a)COO— wherein R_(10a) is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, phenoxymethyl, acetoxymethyl, acyloxymethyl, or methylthiomethyl.

In the “A” series of compounds, X₁₀ is as otherwise as defined herein. Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl, X₁₀ is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R₇ and R₁₀ each have the beta stereochemical configuration.

In the “B” series of compounds, X₁₀ and R_(2a) are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have the beta stereochemical configuration.

In the “C” series of compounds, X₁₀ and R_(9a) are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R_(9a) is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each have the beta stereochemical configuration.

In the “D” and “E” series of compounds, X₁₀ is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R₇, R₉ (series D only) and R₁₀ each have the beta stereochemical configuration.

In the “F” series of compounds, X₁₀, R_(2a) and R_(9a) are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each have the beta stereochemical configuration.

In the “G” series of compounds, X₁₀ and R_(2a) are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each have the beta stereochemical configuration.

In the “H” series of compounds, X₁₀ is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have the beta stereochemical configuration.

In the “I” series of compounds, X₁₀ and R_(2a) are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have the beta stereochemical configuration.

In the “J” series of compounds, X₁₀ and R_(2a) are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each have the beta stereochemical configuration.

In the “K” series of compounds, X₁₀, R_(2a) and R_(9a) are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each have the beta stereochemical configuration.

Any substituents of each X₃, X₅, R₂, R₇, and R₉ may be hydrocarbyl or any of the heteroatom containing substituents selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.

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Series X₅ X₃ R₁₀ R₂ R₉ R₁₄ A1 —COOX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— O H A2 —COX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— O H A3 —CONHX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— O H A4 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— O H substituted C₂ to C₈ alkyl A5 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— O H substituted C₂ to C₈ alkyl A6 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— O H substituted C₂ to C₈ alkyl A7 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— O H substituted C₂ to C₈ alkenyl A8 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— O H substituted C₂ to C₈ alkenyl A9 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— O H substituted C₂ to C₈ alkenyl A10 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— O H substituted C₂ to C₈ alkynyl A11 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— O H substituted C₂ to C₈ alkynyl A12 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— O H substituted C₂ to C₈ alkynyl B1 —COOX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— O H B2 —COX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— O H B3 —CONHX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— O H B4 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— O H substituted C₂ to C₈ alkyl B5 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— O H substituted C₂ to C₈ alkyl B6 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— O H substituted C₂ to C₈ alkyl B7 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— O H substituted C₂ to C₈ alkenyl B8 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— O H substituted C₂ to C₈ alkenyl B9 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— O H substituted C₂ to C₈ alkenyl B10 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— O H substituted C₂ to C₈ alkynyl B11 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— O H substituted C₂ to C₈ alkynyl B12 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— O H substituted C₂ to C₈ alkynyl C1 —COOX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— R_(9a)COO— H C2 —COX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— R_(9a)COO— H C3 —CONHX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— R_(9a)COO— H C4 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkyl C5 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkyl C6 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkyl C7 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkenyl C8 —COX₁₀ optionally R_(10a)OOO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkenyl C9 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkenyl C10 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkynyl C11 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkynyl C12 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkynyl D1 —COOX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— OH H D2 —COX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— OH H D3 —CONHX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— OH H D4 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— OH H substituted C₂ to C₈ alkyl D5 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— OH H substituted C₂ to C₈ alkyl D6 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— OH H substituted C₂ to C₈ alkyl D7 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— OH H substituted C₂ to C₈ alkenyl D8 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— OH H substituted C₂ to C₈ alkenyl D9 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— OH H substituted C₂ to C₈ alkenyl D10 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— OH H substituted C₂ to C₈ alkynyl D11 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— OH H substituted C₂ to C₈ alkynyl D12 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— OH H substituted C₂ to C₈ alkynyl E1 —COOX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— O OH E2 —COX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— O OH E3 —CONHX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— O OH E4 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂ to C₈ alkyl E5 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂ to C₈ alkyl E6 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂ to C₈ alkyl E7 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂ to C₈ alkenyl E8 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂ to C₈ alkenyl E9 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂ to C₈ alkenyl E10 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂ to C₈ alkynyl E11 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂ to C₈ alkynyl E12 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂ to C₈ alkynyl F1 —COOX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— R_(9a)COO— H F2 —COX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— R_(9a)COO— H F3 —CONHX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— R_(9a)COO— H F4 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkyl F5 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkyl F6 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkyl F7 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkenyl F8 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkenyl F9 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkenyl F10 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO H substituted C₂ to C₈ alkynyl F11 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkynyl F12 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkynyl G1 —COOX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— OH H G2 —COX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— OH H G3 —CONHX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— OH H G4 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— OH H substituted C₂ to C₈ alkyl G5 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— OH H substituted C₂ to C₈ alkyl G6 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— OH H substituted C₂ to C₈ alkyl G7 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— OH H substituted C₂ to C₈ alkenyl G8 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— OH H substituted C₂ to C₈ alkenyl G9 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— OH H substituted C₂ to C₈ alkenyl G10 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— OH H substituted C₂ to C₈ alkynyl G11 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— OH H substituted C₂ to C₈ alkynyl G12 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— OH H substituted C₂ to C₈ alkynyl H1 —COOX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— OH OH H2 —COX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— OH OH H3 —CONHX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— OH OH H4 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OH substituted C₂ to C₈ alkyl H5 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OH substituted C₂ to C₈ alkyl H6 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OH substituted C₂ to C₈ alkyl H7 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OH substituted C₂ to C₈ alkenyl H8 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OH substituted C₂ to C₈ alkenyl H9 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OH substituted C₂ to C₈ alkenyl H10 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OH substituted C₂ to C₈ alkynyl H11 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OH substituted C₂ to C₈ alkynyl H12 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OH substituted C₂ to C₈ alkynyl I1 —COOX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— O OH I2 —COX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— O OH I3 —CONHX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— O OH I4 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— O OH substituted C₂ to C₈ alkyl I5 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— O OH substituted C₂ to C₈ alkyl I6 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— O OH substituted C₂ to C₈ alkyl I7 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— O OH substituted C₂ to C₈ alkenyl I8 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— O OH substituted C₂ to C₈ alkenyl I9 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— O OH substituted C₂ to C₈ alkenyl I10 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— O OH substituted C₂ to C₈ alkynyl I11 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— O OH substituted C₂ to C₈ alkynyl I12 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— O OH substituted C₂ to C₈ alkynyl J1 —COOX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— OH OH J2 —COX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— OH OH J3 —CONHX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— OH OH J4 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OH substituted C₂ to C₈ alkyl J5 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OH substituted C₂ to C₈ alkyl J6 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OH substituted C₂ to C₈ alkyl J7 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OH substituted C₂ to C₈ alkenyl J8 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OH substituted C₂ to C₈ alkenyl J9 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OH substituted C₂ to C₈ alkenyl J10 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OH substituted C₂ to C₈ alkynyl J11 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OH substituted C₂ to C₈ alkynyl J12 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OH substituted C₂ to C₈ alkynyl K1 —COOX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— R_(9a)COO— OH K2 —COX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— R_(9a)COO— OH K3 —CONHX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— R_(9a)COO— OH K4 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkyl K5 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkyl K6 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkyl K7 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkenyl K8 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO OH substituted C₂ to C₈ alkenyl K9 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkenyl K10 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkynyl K11 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkynyl K12 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkynyl

EXAMPLE 5 In Vitro Cytotoxicity Measured by the Cell Colony Formation Assay

Four hundred cells (HCT116) were plated in 60 mm Petri dishes containing 2.7 mL of medium (modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin). The cells were incubated in a CO₂ incubator at 37° C. for 5 h for attachment to the bottom of Petri dishes. The compounds identified in Example 2 were made up fresh in medium at ten times the final concentration, and then 0.3 mL of this stock solution was added to the 2.7 mL of medium in the dish. The cells were then incubated with drugs for 72 h at 37° C. At the end of incubation the drug-containing media were decanted, the dishes were rinsed with 4 mL of Hank's Balance Salt Solution (HBSS), 5 mL of fresh medium was added, and the dishes were returned to the incubator for colony formation. The cell colonies were counted using a colony counter after incubation for 7 days. Cell survival was calculated and the values of ID50 (the drug concentration producing 50% inhibition of colony formation) were determined for each tested compound.

IN VITRO Compound ID 50 (nm) HCT116 taxol 2.1 docetaxel 0.6 6577 <1 6515 <1 6066 <1 6111 <1 

1. A method for preparing a pharmaceutical composition comprising mixing at least one nonaqueous, pharmaceutically acceptable solvent and a taxane having the formula

wherein R₂ is acyloxy; R₇ is hydroxy; R₉ is keto, hydroxy, or acyloxy; R₁₀ is R_(10a)COO—; R_(10a) is heterosubstituted methyl, said heterosubstituted methyl moiety lacking a carbon atom which is in the beta position relative to the carbon of which R_(10a) is a substituent; R₁₄ is hydrido or hydroxy; X₃ is substituted or unsubstituted alkyl, alkenyl, or alkynyl or heterocyclo; X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀; X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; and Ac is acetyl.
 2. The method of claim 1 wherein X₃ is heterocyclo.
 3. The method of claim 2 wherein X₅ is —COOX₁₀ and X₁₀ is C₂–C₈ alkyl.
 4. The method of 3 wherein X₁₀ is ethyl or straight or cyclic propyl, butyl, pentyl or hexyl.
 5. The method of claim 3 wherein X₁₀ is branched propyl, pentyl or hexyl.
 6. The method of claim 1 wherein R₉ is hydroxy or acyloxy.
 7. The method of claim 1 wherein R₁₄ is hydroxy.
 8. The method of claim 1 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁–C₈ alkyl, C₂–C₈ alkenyl, or C₂–C₈ alkynyl.
 9. The method of claim 1 wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁–C₈ alkyl, C₂–C₈ alkenyl, or C₂–C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁–C₈ alkyl, C₂–C₈ alkenyl, or C₂–C₈ alkynyl.
 10. The method of claim 1 wherein R_(10a) is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, acetoxymethyl, phenylmethyl or methylthiomethyl.
 11. The method of claim 10 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁–C₈ alkyl, C₂–C₈ alkenyl, or C₂–C₈ alkynyl.
 12. The method of claim 10 wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁–C₈ alkyl, C₂–C₈ alkenyl, or C₂–C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁–C₈ alkyl, C₂–C₈ alkenyl, or C₂–C₈ alkynyl.
 13. The method of claim 8 wherein X₃ is thienyl.
 14. The method of claim 8 wherein X₃ is 2-thienyl.
 15. The method of claim 8 wherein X₃ is furyl.
 16. The method of claim 8 wherein X₃ is 2-furyl.
 17. A method of inhibiting tumor growth in a mammal, said method comprising administering a therapeutically effective amount of a composition comprising at least one pharmaceutically acceptable carrier and a taxane having the formula

wherein X₃ is 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, isobutenyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl; X₅ is —COX₁₀ and X₁₀ is isobutenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, butenyl, or n-propyl or X₅ is —COOX₁₀ and X₁₀ is ethyl, n-propyl, isopropyl, or isobutynyl; R₇ is hydroxy; R₁₀ is R_(10a)COO—; and R_(10a) is heterosubstituted methyl, said heterosubstituted methyl moiety lacking a carbon atom which is in the beta position relative to the carbon of which R_(10a) is a substituent.
 18. The method of claim 17 wherein X₃ is 2-thienyl or 3-thienyl.
 19. The method of claim 17 wherein X₃ is 2-furyl or 3-furyl.
 20. The method of any of claims 17 to 19 wherein R_(10a) is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, acetoxymethyl, phenylmethyl or methylthiomethyl.
 21. The method of claim 20 wherein X₅ is —COOX₁₀ and X₁₀ is ethyl, n-propyl, isopropyl, or isobutyl.
 22. The method of claim 20 wherein X₅ is —COX₁₀ and X₁₀ is isobutenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, butenyl, or n-propyl.
 23. A method of inhibiting tumor growth in a mammal, said method comprising administering a therapeutically effective amount of a composition comprising at least one pharmaceutically acceptable carrier and a taxane having the formula

wherein R₁₀ is acetyloxyacetyloxy or methoxyacetyloxy; X₃ is 2-furyl; X₅ is —COOX₁₀ and X₁₀ is t-amyl; and Ac is acetyl.
 24. A method of inhibiting tumor growth in a mammal, said method comprising administering a therapeutically effective amount of a composition comprising at least one pharmaceutically acceptable carrier and a taxane having the formula

wherein R₁₀ is methoxyacetyloxy or phenoxyacetyloxy; X₃ is 2-furyl; X₅ is —COX₁₀ and X₁₀ is trans-propenyl; and Ac is acetyl.
 25. A pharmaceutical composition comprising a taxane having the formula

and at least one pharmaceutically acceptable carrier wherein R₂ is acyloxy; R₇ is hydroxy; R₉ is keto, hydroxy, or acyloxy; R₁₀ is R_(10a)COO—; R_(10a) is heterosubstituted methyl, said heterosubstituted methyl moiety lacking a carbon atom which is in the beta position relative to the carbon of which R_(10a) is a substituent; R₁₄ is hydrido or hydroxy; X₃ is substituted or unsubstituted alkyl, alkenyl, or alkynyl or heterocyclo; X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀; X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; and Ac is acetyl.
 26. The composition of claim 25 wherein X₃ is 2-theinyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, isobutenyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl; X₅ is —COX₁₀ and X₁₀ is isobutenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, butenyl, or n-propyl or X₅ is —COOX₁₀ and X₁₀ is ethyl, n-propyl, isopropyl, or isobutyl; R₂ is benzoyloxy; R₇ is hydroxy; R₉ is keto; and R₁₄ is hydrido.
 27. The composition of claim 25 wherein R₁₀ is acetyloxyacetyloxy or methoxyacetyloxy; X₃ is 2-furyl; X₅ is —COOX₁₀ and X₁₀ is t-amyl; and Ac is acetyl.
 28. The composition of claim 25 wherein R₁₀ is methoxyacetyloxy or phenoxyacetyloxy; X₃ is 2-furyl; X₅ is —COX₁₀ and X₁₀ is trans-propenyl; and Ac is acetyl. 